One driver to develop new insecticides has been the desire to replace toxic and irksome insecticides. The notorious DDT was introduced as a safer alternative to the then-used lead and arsenic compounds. When used under the correct conditions, almost any chemical substance is safe. However, when used under the wrong conditions, most insecticides can be a threat to health and/or the environment.
Some insecticides have been banned because that they are persistent toxins that adversely affect animals and/or humans. Dichloro Diphenyl Trichloroethane (DDT) is an example of a widely used (and maybe misused) pesticide. One impact of DDT is that it reduces the thickness of the egg shells from predatory birds. Such shells lack viability due to the thin shell causing reductions in predatory bird populations. DDT and a number of related compounds cause such thin shells due to the process of bioaccumulation.
Bioaccumulation is where the chemical accumulates in fat present in the animals due to the chemical's stability and fat solubility. Also, DDT may bio-magnify, which causes progressively higher concentrations in the body fat of animals farther up the food chain. The near-worldwide ban on agricultural use of DDT and related chemicals has allowed some birds, such as the peregrine falcon, to recover in recent years.
A number of the organochlorine pesticides have been banned for most uses worldwide. Organochlorine pesticides are globally controlled by the Stockholm Convention on Persistent Organic Pollutants. Organochlorine pesticides include: aldrin, chlordane, DDT, dieldrin, endrin, heptachlor, mirex and toxaphene.
The current urgent need for new and effective insecticides stems, in large part, from the fact that many insect pests have become resistant to currently available insecticides. (Denholm et al. 2002, “Insecticide resistance on the move,” Science 297:2222-2223).
Hence, there exists a tremendous long-felt need for insecticides, pesticides, ovicides and larvicides that are effective against pests, that are non-toxic to animals and humans, and that do not adversely impact the environment or ecosystem.
Sterol carrier protein-2 (SCP-2) is a conserved intracellular sterol carrier protein. (Gallegos A M et al., Gene structure, intracellular localization, and functional roles of sterol carrier protein-2, Prog Lipid Res 2001 40(6):498-563). SCP-2 was reported in early literature as related to delivery of cholesterol from preformed stores to and into mitochondria for initiation of steroid hormone synthesis. (Chanderbhan R et al., Sterol Carrier Protein2: Delivery of cholesterol from adrenal lipid droplets to michchondria for pregnenolone synthesis, J Bio Chem 1982 257(15):8928-8934). SCP-2 binds lipids in both vertebrate and insect systems, whereby its affinity for cholesterol is much greater than its affinity for fatty acids.
While studying the mosquito sterol carrier protein (AeSCP-2), it has been reported that there exists conversed and divergent functions between vertebrate and invertebrate SCP-2. (Dyer et al., 2003, “The structural determination of an insect sterol carrier protein-2 with a ligand bound C16 fatty acid at 1.35 Å resolution,” J Biol Chem 278:39085-39091).
Several small molecules have been reported as inhibitors to the mosquito SCP-2, whereby the compounds are also reported to be lethal to both mosquitoes and tobacco hornworms likely due to a reduction in cholesterol uptake, whereby the toxicity of N-(4-{[4-(3,4-dichlorophenyl)-1,3-thiazol-2-yl]amino}phenyl)acetamide in mice has also been reported. (Kim M S et al., Identification of mosquito sterol carrier protein-2 inhibitors, J Lipid Res 2005 46(4):650-657). SCP-2 knockouts in mice have been reported to reduce the percentage of cholesterol absorbed in the intestine. (Fuchs M et al., Disruption of the sterol carrier protein 2 gene in mice impairs biliary lipid and hepatic cholesterol metabolism, J Biol Chem 276(51):48058-48065).
It has also been reported that ethanol inhibits lipid binding to SCP-2. (Avdulov N A et al., Lipid binding to sterol carrier protein-2 is inhibited by ethanol, Biochimica et Biophysica Acta 1999 1437:37-45).
SCP-2 over-expression enhances cholesterol uptake in both mammalian and mosquito cultured cells. (Moncecchi D et al., Sterol carrier protein-2 expression in mouse L-cell fibroblasts alters cholesterol uptake, Biochim Biophys Acta 1996 1302(2):110-116; Lan Q et al., 2004, “Subcellular localization of mosquito sterol carrier protein-2 and sterol carrier protein-x, J. Lipid Res. 45(8): 1468-1474).).
AeSCP-2 is a mosquito sterol carrier protein-2. Plants and insects have evolved over millions of years. Many plants produce natural compounds that are insecticidal as a mechanism of self-defense. For example, pyrethrin is a natural insecticide produced by certain species of the chrysanthemum plant. (Elliott M, 1976, “Properties and applications of pyrethroids,” Environ Health Perspect. 14:1-2).
Pyrethroids are synthetic derivatives of pyrethrin. Pyrethroids are widely used insecticides in the developed countries due to low toxicity to vertebrate species and low environmental impact.
It has been reported that α-mangostin has been identified as useful for inhibiting cholesterol-binding in SCP-2 via the high throughput screening method. (Kim M S et al., 2005, “Identification of mosquito sterol carrier protein-2 inhibitors,” i J. Lipid Res. 46(4):650-7).
α-Mangostin has been shown to be effective against certain cancer cells even though the mechanism is unknown to date. (Laphookhieo S et al., 2006, Cytotoxic and antimalarial prenylated xanthones from Cratoxylum cochinchinense, Chem Pharm Bull (Tokyo) 54(5):745-7; and Suksamrarn S et al., 2006, Cytotoxic prenylated xanthones from the young fruit of Garcinia mangostana, Chem Pharm Bull (Tokyo). 54(3):301-5). Others have reported that α-Mangostin reduces rotavirus infectivity, however, the mechanism is unknown. (Shaneyfelt M E et al., 2006, Natural products that reduce rotavirus infectivity identified by a cell-based moderate-throughput screening assay, Virol J. 3:68).